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Wednesday, August 3, 2011

Mammography and breast cancer mortality: correlation is not causation

Breast cancer mortality has been declining in the industrialized world over the last several decades. At the same time, mammographic screening has become the norm in most of Europe, Australia and North America. Does early detection explain the reduced mortality? A paper in the Aug 1 British Medical Journal concludes that it does not.

The study looked at three country pairs (Northern Ireland vs the Republic of Ireland, the Netherlands vs Belgium and Flanders, and Sweden vs Norway), in which breast cancer screening was introduced at different time periods. The paper points out that it would not be unprecedented for screening to lead to lower death rates because that's exactly what happened with cervical cancer mortality, which quickly decreased in the countries in which it was first introduced, with a lag time as others adopted the practice. That seems clearly because early detection led to curative treatment.

Thus, the researchers decided to test the idea that mortality from breast cancer fell first in countries that first had high screening rates (for the purposes of this study, over 70%). So, they looked at breast cancer mortality in these neighboring pairs of countries, which happened to have implemented screening many years apart, and they controlled for confounding factors that might have influenced mortality risk.

All data were population data: breast cancer death rates for each country were drawn from a World Health Organization mortality database, and confounding variables (obesity, age at first birth and total fertility, all of which have been shown to affect risk of breast cancer) from nation-wide statistics on these, by age. Data on breast cancer management was also population-based; they looked at expenditures on anticancer drugs, the 'uptake of new anticancer drugs in general...after their introduction in the country, and the uptake of trastuzumab [a recently introduced cancer medication that is effective against a subset of breast tumors]...after its introduction in the country.'

National organized screening was first introduced in Sweden in1986, and by 1990 90% of Swedish women had been offered a screening. Screening rates there are among the highest in any country. In Norway, in contrast, organized screening wasn't introduced until 1996 as a pilot project, and was gradually expanded until in 2005 the program was nationwide. Breast cancer mortality fell by 16% in Sweden and by 24% in Norway between 1989 and 2006.

Mammography screening and mortality, Sweden and Norway

Trends are similar in the Netherlands and Belgium, with organized screening beginning in 1989 in the former, and not until 2001 in the latter, with only 59% of Belgian women undergoing screening by 2005. Breast cancer mortality fell by 25% in the Netherlands from 1989 to 2006, and by 19.9% in Belgium, but by 24.6% in Flanders.

Finally, screening began in the 1990s in Northern Ireland, but was first introduced in the Republic of Ireland in 2000, and it wasn't until 2008 that more than 70% of women over 50 were screened. Breast cancer mortality decreased by 29.6% in Northern Ireland and by 26.7% in the Republic of Ireland between 1989 and 2006.

The authors report that, at the population level, obesity levels and reproductive variables didn't differ significantly between countries, and cancer treatment, measured by drug expenditures, didn't differ significantly between countries, though uptake of recent drugs seemed to be slower in Norther Ireland than other countries.

This is a population-based study, which means that confounding variables can't be linked to individuals. Thus, for example, it's possible that obesity rates differ significantly among women who undergo mammography and those who don't. Given this limitation, the study concludes

The contrast between the timing of breast cancer screening being implemented and the similarity in mortality reduction between the country pairs do not suggest that a large proportion of the mortality reduction after 1990 can be attributed to mammography screening. Improvements in treatment and in the efficiency of healthcare systems may be more plausible explanations. Our study adds further population data to the evidence of studies that have used various designs and found that mammography screening by itself has little detectable impact on mortality due to breast cancer.

Given that there is a small, perhaps even undetectable, increase in risk of breast cancer due to exposure to the screening process itself, this study is another that gives pause to the idea that all women over either 40 or 50, depending on who is doing the recommending, would benefit from routine annual, or biannual, mammography. X-ray screening for breast cancer is, however, a practice by now considered by many to be state-of-the-art medical care for women in many countries, and previous attempts to recommend that its use be curtailed, based on similar findings in 2009, met with loud and widespread disapproval.

There is the other fact that mammography leads to early diagnosis and intervention, but that means (1) higher rates of reported cases and (2) morbidity and trauma (including psychological) due to the treatment of the detected tumors. But evidence we discussed in earlier posts (here and here) showed that many of those tumors would have resolved on their own, needing no treatment. So even if lifestyles are responsible for the overall reduction in cases, screening has the potential negative effect of over-diagnosis.

The fact that mammography is big business can't be ignored here. Just as DNA sequencing is big business, and it's in the interest of sequencing manufacturers for science to find more uses for their machines, the makers of mammographic equipment, as well as mammography clinics, can't take kindly to the idea that women might need less screening.

But even if we don't throw the complicating factor of vested interests into the mix, as with other health issues that are studied on the population level, it's difficult to know how to apply these results to individuals. Population-level data lead to population-level recommendations. That is the job of public health, of course, so the problem is not simple. In 2009, much of the negative reaction to the recommendations for less screening came from women who testified that mammography saved their life. Surely there are such instances, but given the vagaries of tumor type, stage at which it's found, speed of growth, response to chemotherapy and so forth, which they are is hard, if not impossible to determine. And certainly impossible to predict.

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